Cell surface receptors are, in general, excellent and validated drug targets. nAChRs comprise a large family of ligand-gated ion channels that control neuronal activity and brain function. These receptors have a pentameric structure. In mammals, this gene family is composed of nine alpha and four beta subunits that co-assemble to form multiple subtypes of receptors that have a distinctive pharmacology. Acetylcholine is the endogenous regulator of all of the subtypes, while nicotine non-selectively activates all nAChRs.
The α7 nAChR is one receptor system that has proved to be a difficult target for testing. Native α7 nAChR is not routinely able to be stably expressed in most mammalian cell lines (Cooper and Millar, J. Neurochem., 1997, 68(5):2140-51). Another feature that makes functional assays of α7 nAChR challenging is that the receptor is rapidly (100 milliseconds) inactivated. This rapid inactivation greatly limits the functional assays that can be used to measure channel activity.
Recently, Eisele et al. has indicated that a chimeric receptor formed between the N-terminal ligand binding domain of the α7 nAChR (Eisele et al., Nature, 366(6454), p 479-83, 1993), and the pore forming C-terminal domain of the 5-HT3 receptor expressed well in Xenopus oocytes while retaining nicotinic agonist sensitivity. Eisele et al. used the N-terminus of the avian (chick) form of the α7 nAChR receptor and the C-terminus of the mouse form of the 5-HT3 gene. However, under physiological conditions the α7 nAChR is a calcium channel while the 5-HT3R is a sodium and potassium channel. Indeed, Eisele et al. teaches that the chicken α7 nAChR/mouse 5-HT3R behaves quite differently than the native α7 nAChR with the pore element not conducting calcium but actually being blocked by calcium ions. WO 00/73431 A2 reports on assay conditions under which the 5-HT3R can be made to conduct calcium. This assay may be used to screen for agonist activity at this receptor.
WO 00/73431 A2 discloses two binding assays to directly measure the affinity and selectivity of compounds at the α7 nAChR and the 5-HT3R. The combined use of these functional and binding assays may be used to identify compounds that are selective agonists of the α7 nAChR.
U.S. Pat. No. 5,977,144 discloses compositions for benzylidene- and cinnamylidene-anabaseines and methods for using these compositions for treating conditions associated with defects or malfunctioning of nicotinic subtypes brain receptors. These compositions target the α7 receptor subtype with little or no activation of the α4β2 or other receptor subtypes.
U.S. Pat. No. 5,599,937 discloses heteroaromatic quinuclidines used for treating diseases related to muscarinic receptor function.
U.S. Pat. No. 5,561,149 discloses the use of a mono or bicyclic carbocyclic, or heterocyclic carboxylic acid, ester or amide or an imidazolyl carbazol in the manufacture of a medicament suitable for the treatment of stress-related psychiatric disorders, for increasing vigilance, for the treatment of rhinitis or serotonin-induced disorders and/or coadministration with another active agent to increase the bioavailability thereof, or for nasal administration.
U.S. Pat. No. 5,543,426 discloses the use of certain 3,7-disubstituted indole compounds for treating depression or cognitive disorders.
U.S. Pat. No. 5,434,161 discloses imidazopyridines as serotonergic 5-HT3 antagonists.
U.S. Pat. No. 5,362,740 discloses dihydrobenzofuran carboxamides useful in treating CNS disorders, but motility disorders, and/or emisis and/or pain in mammals, and/or migraine.
U.S. Pat. No. 5,342,845 discloses indole derivatives and drugs. The compound of the invention is disclosed as being effective as a gastrointestinal motor activity regulator, antimigraine, antipsychotic or antianxiety drug and for dementia or orthostatic hypotension.
U.S. Pat. No. 5,322,951 discloses certain 1-(2,3-dihydro-indole)carbonyl intermediates useful for preparing 1-(2,3-dihydro)-1-carboxamide final products that possess 5-HT M-receptor antagonist activity.
U.S. Pat. No. 5,183,822 discloses substituted 3,4-Annelated Benzimidazole-2(1H)-ones as being active as 5-HT receptor antagonists.
U.S. Pat. No. 5,063,231 discloses a method of treatment of visceral pain.
U.S. Pat. No. 5,039,680 discloses 5-HT3 antagonists in preventing or reducing dependency on dependency-inducing agents.
U.S. Pat. No. 5,001,133 discloses substituted benzoic acid heterocyclic amides and esters as being serotonin M antagonists.
U.S. Pat. No. 4,985,437 discloses the use of certain compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT3 receptors for the treatment of cognitive disorders such as attentional and memory deficits and dementia states.
U.S. Pat. No. 4,983,600 discloses heterocyclic compounds useful as 5-HT3 antagonists.
U.S. Pat. No. 4,973,594 discloses the use of compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT3 receptors for the treatment of depression.
U.S. Pat. No. 4,937,247 discloses 1-acyl indazoles that are disclosed as having 5-HT3 antagonist activity.
U.S. Pat. No. 4,935,511 discloses benzoxazine and benzoxazepin carboxamide 5-HT3 antagonists properties including CNS, anti-emetic and gastric prokinetic activity and which are void of any significant D2 receptor binding affinity.
U.S. Pat. No. 4,933,445 discloses heteroazabenzobicyclic carboxamide 5-HT3 antagonists.
U.S. Pat. No. 4,921,982 discloses 5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acids which are useful as intermediates for 5-HT3 antagonists.
U.S. Pat. No. 4,920,219 discloses substituted saturated and unsaturated indole quinoline and benzazepine carboxamides and their valuable use as 5-HT3 antagonists having CNS and gastric prokinetic activity void of any significant D2 receptor binding properties.
U.S. Pat. No. 4,920,127 discloses substituted indoles and their use as 5-HT3 receptor antagonists.
U.S. Pat. No. 4,910,193 discloses treatment of gastrointestinal disorders. U.S. Pat. No. 4,882,327 discloses certain heterocyclic N-substituted carboxamides having 5-HT3 receptor antagonist activity.
U.S. Pat. No. 4,863,919 discloses a method of enhancing memory or correcting memory deficiency with arylamido (and arylthioamido)-azabicycloalkanes.
U.S. Pat. No. 4,835,162 discloses agonists and antagonists to nicotine as smoking deterrents.
U.S. Pat. No. 4,822,795 discloses pharmaceutically useful esters and amides.
U.S. Pat. No. 4,803,199 discloses pharmaceutically useful heterocyclic acid esters and amides or alkylene bridged peperidines as serotonin M antagonists.
U.S. Pat. No. 4,798,829 discloses 1-azabicyclo[3.2.2]nonane derivatives having gastric motility enhancing activity and/or anti-emetic activity and/or 5-HT receptor antagonist activity.
U.S. Pat. No. 4,797,406 discloses amides and esters containing bridged piperidines and use as serotonin M antagonists.
U.S. Pat. No. 4,721,720 discloses a method of treating emesis, anxiety and/or irritable bowl syndrome.
U.S. Pat. No. 4,612,319 discloses bridged quinolizinidinylamides, compositions containing them and methods for their use.
WO 01/76576 A2 discloses a pharmaceutical composition for treatment of acute, chronic pain and/or neuropathic pain and migraines.
WO 01/60821 A1 discloses novel biarylcarboxamides and their use in therapy, especially in the treatement of prophylaxis of psychotic and intellectual impairment conditions.
WO 01/36417 Al discloses novel N-azabicyclo-amide derivatives and use in therapy, especially in the treatment of prophylaxis of psychotic disorders and intellectual impairment disorders.
WO 99/20633 discloses benzoazine derivatives having an antagonist activity for 5-HT3/5-HT4 receptors.
WO 97/35860 discloses novel benzimidazol derivatives having an affinity for the serotoninergic 5-HT3/5-HT4 receptors.
WO 95/27490 discloses serotonin antagonists (5-HT3) for treating fibromyalgia.
WO 95/04742 discloses tropyl 7-azaindol-3-ylcarboxyamides as antitussive agents.
WO 93/06108 discloses pyrrolobenzoxazine derivatives as 5-HT agonists and antagonists.
WO 91/17161 discloses isoquinoline amides and esters as 5-HT3 receptor antagonists.
WO 91/09593 discloses 5-HT3 antagonists for treatment of nausea, bradycardia or hypotension associated myocardial instability.
WO 90/14347 A as abstracted in chemical abstract 1991:143,158 discloses N-quinuclidinyl-indolecarboxamide derivatives as being antiemetics.
EP 512 350 A2 discloses 3-(indolyl-2-carboxamido) quinuclidines useful for treating diseases characterized by an excess or enhanced sensitivity to serotonin, e.g., psychosis, nausea, vomiting, dementia or other cognitive diseases, migraine, diabetes. The compound may be used to control anxiety, aggression, depression, and pain. The compounds are disclosed as serotonin 5-HT3 antagonists.
EP 483 836 A1 discloses pyrazolo[1,5-a]pyridine-3-carboxylic acid derivatives, their preparation process, and serotonin receptor antagonists containing them as active ingredients.
DE 3810552 A1 discloses esters and amides of indolyl-, benzo[b]thiophenyl-, benzo[b]furancarboxylic acids or 4-amino-2 methoxy-benzoic acids with N-heterocyclic or N-heterobicyclic alcohols or amines. The compounds disclosed have activity against pain especially migraine, as an anti-arrhythmic for gastrointestinal disturbances, stomach disturbances, gastritis ulcer, gall bladder, spastic colon, Crohn's disease, ulcerative colitis, carcinoid syndrome, diarrhea of various types. The compounds are also disclosed as speeding stomach emptying, controlling gastro duodenal and gastro esophageal reflux, disturbances of esophageal motility, hiatal hernia, cardiac insufficiency, hypotonic stomach, paralytic ileus, manic depressive psychosis and other psychoses. The compounds are also disclosed as useful for stress related diseases, senility, and enhancement of nasal absorption of other agents, e.g., in the treatment of emesis.
In Bioorg. & Med.Chem. Lett. 11 (2001) 319-321, the 5-HT3 antagonist tropisetron (ICS 205-930) is discussed as a potent and selective α7 nicotinic receptor partial agonist.
In Behavioral Brain Res., 113 (2000) 169-181, it is discussed that the brain α7 nicotinic receptor may be an important therapeutic target for the treatment of Alzheimer's disease using DMXBA which is known as GTS-21.
In Bioorg. & Med. Chem. Lett. 9 (1999) 1895-1900, it is discussed the discovery of a highly potent, functionally-selective muscarinic M1 agonist.
In Bioorg. & Med. Chem. Lett. 4 (1994) 695-698, it is discussed pyrazolo[1,5-a]pyridines and pyrazolo[1,5-b]pyridazines as 5-HT3 antagonists.
In Eur. J.Med. Chem., 34 (1999) 415-422, benzimidazole-2-carboxylic acid amides and esters are discussed as a new structural class of 5-HT3 ligands.